The recent US Food and Drug Administration’s warning on non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) has once again highlighted the potential risk associated with the use of these medicines. Following the voluntary withdrawal of rofecoxib (Vioxx), a cox II inhibitor, from the international market due to increased cardiovascular events among the users in 2004, has generated lot of interest on safety aspects of non-aspirin non-steroidal anti-inflammatory drugs. The European Medicine Agency (EMA) earlier confirmed the increased risk of thrombotic complications associated with their use. The US Food and Drug Administration, perhaps most stringent drug regulatory authority in the globe, warned on 9th July 2015 “Non-aspirin non-steroidal anti-inflammatory drugs increase the chance of a heart attack or stroke”. It urges the patients taking non-aspirin non-steroidal anti-inflammatory drugs to seek medical attention immediately if they experience symptoms such as chest pain, shortness of breath or trouble breathing, weakness in one part or side of their body, or slurred speech.
The US Food and Drug Administration’s first alert was issued in the form of box warning on the risk of heart attack and stroke with non-aspirin non-steroidal anti-inflammatory drugs leading to death during 2005. Since then these medicines have been under safety watch. Based on the recent review of safety information and on the advice of advisory committees, US Food and Drug Administration advised the change in labelling of prescription non-aspirin NSAIDs. The revised label should reflect the following information: the risk of heart attack or stroke can occur as early as first week of using non-aspirin non-steroidal anti-inflammatory drugs; the risk may increase with higher dose and longer use; increased risk of heart attack or stroke with or without heart disease or risk factors; patient treated with non-aspirin non-steroidal anti-inflammatory drugs following first heart attack is more likely to die in the first year; and an increased risk of heart failure.
However, the US Food and Drug Administration’s warning is less clear and perhaps confusing too on the comparative risk of various non-aspirin non-steroidal anti-inflammatory drugs. The regulator says “there is no sufficient information to determine that the risk of any particular non-aspirin non-steroidal anti-inflammatory drug is definitely higher or lower than that of any other particular NSAID”. Cardiovascular events are not the only issue of non-aspirin non-steroidal anti-inflammatory drugs; they are associated with other adverse events too. All these medicines have potential to cause irritation and even gastric ulcers. The incidences of NSAID induced gastric ulcers are not uncommon. In order to prevent gastric irritation, the patients are advised to swallow these medicines after meal and not to take in empty stomach. The physicians advise either H2 blockers or Proton Pump Inhibitors, who reduce production of gastric secretion, along with the NSAID to reduce the gastric side effects. But these two groups of medicines too have their share of side effects. Taking one drug to minimise the adverse events of the other(s) is not always a good solution.
In 2012, the US Food and Drug Administration issued guidance to industries for issuing organ specific warning for analgesics, antipyretics and anti-rheumatic drugs including for paracetamol. In last year 2014, the Government of India restricted the use of two pain killers: tramadol and tapentadol. The government directed that the labels, package inserts, and other promotional materials be revised based on the recommendation of drug advisory committee. The government directed that these two drugs as well as their combinations should be restricted to severe acute pain for a period not exceeding five days since these medicines have potential to cause respiratory depression and addiction. The government of India is yet to react on recent US Food and Drug Administration’s warning and is expected to issue similar alert in public health interest.
Topical use of non-aspirin non-steroidal anti-inflammatory drugs is reported to be much safer but equally effective in pain management. A recent Cochrane review confirmed the effectiveness of topical non-aspirin non-steroidal anti-inflammatory drugs is similar to that of orally administered ones. The study compared the effects of non-aspirin non-steroidal anti-inflammatory drugs in the form of gel, spray, or cream. Formulations of topical diclofenac, ibuprofen, ketoprofen, piroxicam, and indomethacin demonstrated significantly higher rates of clinical success than matching topical placebo. Gel formulations of diclofenac (as Emugel), ibuprofen, and ketoprofen, and some diclofenac patches, provided the best effects. The adverse events reported were very minimal. Local skin reactions were mild and transient and similar to placebos.
It is reasonable to conclude that all non-aspirin non-steroidal anti-inflammatory drugs cannot have equal risks of fatal adverse events like heart attack or stroke. Some may be more harmful than others. Some studies have shown that diclofenac is ahead of others in its potential to harm the patients due to its high cardiovascular risk. Diclofenac can even cause animal toxicity if unused or expired medicines are not appropriately disposed. Its use in animal is prohibited. While diclofenac is at the top of the risk ladder, naproxen is reported to be at the bottom. Naproxen has reported to have lower cardiovascular risk profile.
The non-aspirin non-steroidal anti-inflammatory drugs have wide use in clinical practice and are mainstay for the treatment of painful conditions and many patients rely on them for their daily routine works. They have been in use for a variety of conditions such as arthritis, low back pain and soft tissue pain. They are also used to treat pain and fever associated with cold and fever. In spite of the risks involved in using them, their use is indispensible. Comparative efficacy studies have shown they have comparable efficacy none showing a significant benefit over the others. The sensitization and education of healthcare professionals including patients on safe and effective use would minimize the harm associated with the use of non-aspirin non-steroidal anti-inflammatory drugs. Three key points should be the guiding principles: Select the non-aspirin non-steroidal anti-inflammatory drug with lowest risk profile, use lowest effective dose and use for the shortest time possible.
(Authors are professors with Department of Pharmacy, Annamalai University, Annamalai Nagar, Tamil Nadu 608 002)